Actinonin, a Naturally Occurring Antibacterial Agent, Is a Potent Deformylase Inhibitor

Chen, Dawn Z.; Patel, Dinesh V.; Hackbarth, C J; Wang, Wen; Dreyer, Geoffrey B.; Young, Dennis C.; Margolis, Peter; Wu, Charlotte; Ni, Zi-Jie; Trias, Joaquim; White, Richard; Yuan, Zhengqiu

doi:10.1021/bi992245y

Cited by 287 publications

(220 citation statements)

References 37 publications

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“…Actinonin is synthesized by actinomycetes (4), and it inhibits bacterial growth in a bacteriostatic manner (5,6). Unlike protein synthesis in eukaryotes, where translation is initiated with a nonformylated methionyl (Met) initiator tRNA (tRNAi), most eubacteria initiate translation with a formylated Met-tRNAi (5,7).…”

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Reducing the fitness cost of antibiotic resistance by amplification of initiator tRNA genes

Nilsson

Zorzet²,

Kanth³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

121

114

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Deformylase inhibitors belong to a novel antibiotic class that targets peptide deformylase, a bacterial enzyme that removes the formyl group from N-terminal methionine in nascent polypeptides. Using the bacterium Salmonella enterica, we isolated mutants with resistance toward the peptide deformylase inhibitor actinonin. Resistance mutations were identified in two genes that are required for the formylation of methionyl (Met) initiator tRNA (tRNAi) fMet : the fmt gene encoding the enzyme methionyl-tRNA formyltransferase and the folD gene encoding the bifunctional enzyme methylenetetrahydrofolate-dehydrogenase and -cyclohydrolase. In the absence of antibiotic, these resistance mutations conferred a fitness cost that was manifested as a reduced growth rate in laboratory medium and in mice. By serially passaging the low-fitness mutants in growth medium without antibiotic, the fitness costs could be partly ameliorated either by intragenic mutations in the fmt͞folD genes or by extragenic compensatory mutations. Of the extragenically compensated fmt mutants, approximately one-third carried amplifications of the identical, tandemly repeated metZ and metW genes, encoding tRNAi. The increase in metZW gene copy number varied from 5-to 40-fold and was accompanied by a similar increase in tRNAi levels. The rise in tRNAi level compensated for the lack of methionyl-tRNA formyltransferase activity and allowed translation initiation to proceed with nonformylated methionyl tRNAi. Amplified units varied in size from 1.9 to 94 kbp. Suppression of deleterious mutations by gene amplification may be involved in the evolution of new gene functions. compensatory evolution ͉ gene amplification ͉ Salmonella typhimurium ͉ actinonin ͉ peptide deformylase

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“…These steps are often required for the nascent polypeptide to mature into a functional protein (1,8). Actinonin inhibits PDF, leading to accumulation of toxic formylated polypeptides in the cell and subsequent growth inhibition (5,6).…”

mentioning

confidence: 99%

Reducing the fitness cost of antibiotic resistance by amplification of initiator tRNA genes

Nilsson

Zorzet²,

Kanth³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

121

114

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“…The structural comparison of several PDFs in complex with an inhibitor has provided guidelines for the design of high affinity PDF inhibitors (PDF-In) (16,19). Actinonin, a pseudotripeptide hydroxamate derivative, has been shown to target peptide deformylases specifically and therefore to have natural antibiotic activity (24,25). Many actinonin derivatives have been synthesized and shown to display potent antibiotic activity (26).…”

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confidence: 99%

The Crystal Structure of Mitochondrial (Type 1A) Peptide Deformylase Provides Clear Guidelines for the Design of Inhibitors Specific for the Bacterial Forms

Fieulaine

Juillan-Binard

Serero

et al. 2005

Journal of Biological Chemistry

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Peptide deformylase (PDF) inhibitors have a strong potential to be used as a new class of antibiotics. However, recent studies have shown that the mitochondria of most eukaryotes, including humans, contain an essential PDF, PDF1A. The crystal structure of the Arabidopsis thaliana PDF1A (AtPDF1A), considered representative of PDF1As in general, has been determined. This structure displays several similarities to that of known bacterial PDFs. AtPDF1A behaves as a dimer, with the C-terminal residues responsible for linking the two subunits. This arrangement is similar to that of Leptospira interrogans PDF, the only other dimeric PDF identified to date. AtPDF1A is the first PDF for which zinc has been identified as the catalytic ion. However, the zinc binding pocket does not differ from the binding pockets of PDFs with iron rather than zinc. The crystal structure of AtPDF1A in complex with a substrate analog revealed that the substrate binding pocket of PDF1A displays strong modifications. The S1 binding pocket is significantly narrower, due to the creation of a floor from residues present in all PDF1As but not in bacterial PDFs. A true S3 pocket is created by the residues of a helical CD-loop, which is very long in PDF1As. Finally, these modified substrate binding pockets modify the position of the substrate in the active site. These differences provide guidelines for the design of bacterial PDF inhibitors that will not target mitochondrial PDFs.

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“…Actinonin, a naturally occurring hydroxamic acid pseudopeptide, is a potent inhibitor of bacterial PDFs. 5 Until now, no structure has been reported for complexes of S. aureus PDF (SaPDF; class II PDF) with any inhibitors. In order to provide the missing structural data, we have determined the crystal structure of SaPDF in complex with its inhibitor actinonin at 1.90 Å resolution.…”

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Crystal structure of peptide deformylase from Staphylococcus aureus in complex with actinonin, a naturally occurring antibacterial agent

et al. 2004

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Actinonin, a Naturally Occurring Antibacterial Agent, Is a Potent Deformylase Inhibitor

Cited by 287 publications

References 37 publications

Reducing the fitness cost of antibiotic resistance by amplification of initiator tRNA genes

Reducing the fitness cost of antibiotic resistance by amplification of initiator tRNA genes

The Crystal Structure of Mitochondrial (Type 1A) Peptide Deformylase Provides Clear Guidelines for the Design of Inhibitors Specific for the Bacterial Forms

Crystal structure of peptide deformylase from Staphylococcus aureus in complex with actinonin, a naturally occurring antibacterial agent

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